Pain is a subjective experience with affective and cognitive components, an "unpleasant sensory and emotional experience associated with actual or potential tissue damage that serves an essential role in alerting an individual to potentially harmful stimuli in the environment". But chronic pain, often disabling and refractory to treatment, represents a difficult medical problem with enormous societal impact. Herpes simplex virus (HSV) naturally targets with high efficiency to neurons of the dorsal root ganglion (DRG) from peripheral inoculation. We have demonstrated that HSV based vectors can be used to transduce neurons of the DRG to achieve an antinociceptive effect in models of inflammatory pain, neuropathic pain, and pain resulting from tumor in bone. The effect is local, synergistic with morphine, and persists despite tolerance to morphine. The preclinical data for this novel approach to the treatment of pain is compelling. In response to the RFA, we propose a series of studies to investigate the hypothesis that HSV-mediated gene transfer to the DRG may be used to treat chronic pain. These studies are designed to overcome the barriers that stand between preclinical proof-of-principle experiments and the development of a treatment for the human disease, and to create novel vectors to enhance gene therapy for specific types of pain. Five specific aims are outlined. Specific Aim 1. To define the duration and dose-response characteristics of the vector-mediated analgesic effect. Specific Aim 2. To construct a vector with a regulatable "switch" to control vector-mediated enkephalin expression in vivo. Specific Aim 3. To test the effect of prior immunity on vector transduction, the potential of the recombinant vector to reactivate latent virus, and to study the level and kinetics of the anti-nociceptive response following repeated vector re-inoculation. Specific Aim 4. To systematically evaluate biodistribution and biosafety of the recombinant enkephalin expressing vector in rodents. Specific Aim 5. To create and test novel HSV-based vectors in models of neuropathic, inflammatory, and cancer pain.